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Background: Tumour-infiltrating lymphocytes (TILs) are associated with improved survival in several epithelial cancers. The two chemokines CXCL9 and CXCL10 facilitate chemotactic recruitment of TILs, and their intratumoral accumulation is a conceivable way to improve TIL-dependent immune intervention in cancer. However, the prognostic impact of CXCL9 and CXCL10 in high-grade serous ovarian cancer (HGSC) is largely unknown. Methods: One hundred and eighty four cases of HGSC were immunohistochemically analyzed for CXCL9, CXCL10. TILs were assessed using CD3, CD56 and FOXP3 staining. Chemokine regulation was investigated using the ovarian cancer cell lines OV-MZ-6 and SKOV-3. Results: High expression of CXCL9 and CXCL10 was associated with an approximately doubled overall survival ( n =70, CXCL9: HR 0.41; P =0.006; CXCL10: HR 0.46; P =0.010) which was confirmed in an independent validation set ( n =114; CXCL9: HR 0.60; P =0.019; CXCL10: HR 0.52; P =0.005). Expression of CXCR3 ligands significantly correlated with TILs. In human ovarian cancer cell lines the cyclooxygenase (COX) metabolite Prostaglandin E2 was identified as negative regulator of chemokine secretion, whereas COX inhibition by indomethacin significantly upregulated CXCL9 and CXCL10. In contrast, celecoxib, the only COX inhibitor prospectively evaluated for therapy of ovarian cancer, suppressed NF- κ B activation and inhibited chemokine release. Conclusion: Our results support the notion that CXCL9 and CXCL10 exert tumour-suppressive function by TIL recruitment in human ovarian cancer. COX inhibition by indomethacin, not by celecoxib, may be a promising approach to concomitantly improve immunotherapies.

BackgroundResponse to immune checkpoint blockade (ICB) in ovarian cancer remains disappointing. Several studies have identified the chemokine CXCL9 as a robust prognosticator of improved survival in ovarian cancer and a characteristic of the immunoreactive subtype, which predicts ICB response. However, the function of CXCL9 in ovarian cancer has been poorly studied.MethodsImpact of Cxcl9 overexpression in the murine ID8-Trp53−/− and ID8-Trp53−/–Brca2−/− ovarian cancer models on survival, cellular immune composition, PD-L1 expression and anti-PD-L1 therapy. CXCL9 expression analysis in ovarian cancer subtypes and correlation to reported ICB response.ResultsCXCL9 overexpression resulted in T-cell accumulation, delayed ascites formation and improved survival, which was dependent on adaptive immune function. In the ICB-resistant mouse model, the chemokine was sufficient to enable a successful anti-PD-L1 therapy. In contrast, these effects were abrogated in Brca2-deficient tumours, most likely due to an already high intrinsic chemokine expression. Finally, in ovarian cancer patients, the clear-cell subtype, known to respond best to ICB, displayed a significantly higher proportion of CXCL9high tumours than the other subtypes.ConclusionsCXCL9 is a driver of successful ICB in preclinical ovarian cancer. Besides being a feasible predictive biomarker, CXCL9-inducing agents thus represent attractive combination partners to improve ICB in this cancer entity.

Purpose This study was performed to evaluate skin toxicity during modern three-dimensional conformal radiotherapy (3D-CRT) and to evaluate the importance of dose distribution and patient related factors. Material and methods This study comprises 255 patients with breast cancer treated with tangential three-dimensional conformal radiotherapy (3D-CRT) after breast conserving surgery between 03/2012 and 05/2017. The median prescribed dose was 50.4 Gy (range 50–50.4) and 92.2% of the patients received a sequential boost of 10–16 Gy. Adverse skin toxicities (according to CTCAE v. 4.03 and the occurrence of moist desquamations) were assessed at the end of treatment. The dose distribution in the skin (5 mm strip from the patient outline) and in the CTV was evaluated and correlated to the CTCAE scores and the occurrence of moist desquamation. Results 42.4% of the patients developed grade I, 55.7% grade II and 2% grade III skin toxicities. Moist desquamation was observed in 59 cases (23.1%). Dose distribution within the CTV and skin was homogenous with only small areas receiving 107% of the prescribed dose (median: 0.7 cm 3 ) in the CTV and 105% (median 0.5 cm 3 ) in the skin. On univariate analysis breast size as well as V107%(CTV), V105%(skin) and V80%(skin) correlated significantly ( p  < 0.05) with the incidence of skin toxicity. On multivariate analysis only V80%(skin) was confirmed as independent risk factor. Conclusion Modern tangential multi-field 3D-CRT allows a homogeneous dose distribution with similar skin toxicity as compared to studies performing IMRT. Dose distribution within the skin (V80%) might have a relevant impact on the severity of skin toxicity and the occurrence of moist desquamation.

Background Health benefits of the Mediterranean Diet (MD) have been shown in different at-risk populations. A German translation of the Mediterranean Diet Adherence Screener (MEDAS) from the PREvención con DIeta MEDiterránea (PREDIMED) consortium was used in the LIBRE study, investigating effects of lifestyle-intervention on women with BRCA1/2 mutations. The purpose of the present study is to validate the MEDAS German version. Methods LIBRE is a multicentre (three university hospitals during this pilot phase), unblinded, randomized, controlled clinical trial. Women with a BRCA1/2 mutation of age 18 or over who provided written consent were eligible for the trial. As part of the assessment, all were given a full-length Food Frequency Questionnaire (FFQ) and MEDAS at baseline and after 3 months. Data derived from FFQ was compared to MEDAS in order to evaluate agreement or concordance between the two questionnaires. Additionally, the association of dietary intake biomarkers in the blood (β-carotene, omega-3, omega-6 and omega-9 fatty acids and high-sensitivity C-reactive protein (hsCRP)) with some MEDAS items was analyzed using t-Tests and a multivariate regression. Results The participants of the LIBRE pilot study were 68 in total (33 Intervention, 35 Control). Only participants who completed both questionnaires were included in this analysis (baseline: 66, month three: 54). The concordance between these two questionnaires varied between the items (Intraclass correlation coefficient of 0.91 for pulses at the highest and −0.33 for sugar-sweetened drinks). Mean MEDAS scores (sum of all items) were 9% higher than their FFQ counter-parts at baseline and 15% after 3 months. Higher fish consumption (at least 3 portions) was associated with lower omega-6 fatty acid levels ( p  = 0.026) and higher omega-3 fatty acid levels ( p  = 0.037), both results being statistically significant. Conclusions We conclude that the German MEDAS in its current version could be a useful tool in clinical trials and in practice to assess adherence to MD. Trial registration ClinicalTrials.gov , registered on March 12, 2014, identifier: NCT02087592 . World Health Organization Trial Registration, registered on 3 August 2015, identifier: NCT02087592 .

Purpose Anterior intercostal artery perforator (AICAP) flaps are valuable options for partial breast reconstruction, requiring reliable identification of dominant perforators for safe flap design. This study aimed to evaluate the agreement between preoperative high-frequency colour Doppler ultrasound (CDUS) findings and intraoperative anatomy of internal and lateral intercostal perforators, and to map their anatomical distribution. Methods Sixty-four patients undergoing breast-conserving surgery were examined using high-frequency CDUS. The region from the midline to the mid-axillary line and from the fourth intercostal space to 4 cm below the inframammary fold was systematically scanned. Dominant perforators were measured, marked, and intraoperatively reassessed in 24 patients undergoing AICAP flap reconstruction. Vessel diameters, location, and additional perforators were recorded and spatial distribution was analysed. Results Preoperative CDUS identified lateral perforators as larger than internal (2.08 mm vs. 1.61 mm, p  < 0.01), confirmed intraoperatively (1.69 mm vs. 1.10 mm, p < 0.01). Dominant perforators were located 3.63 cm lateral to the patient’s midline and 1.32 cm inferior to the IMF (internal), and 0.53 cm medial to the anterior axillary line and 0.95 cm inferior to the IMF (lateral). In both internal and lateral regions, supplementary vessels were detected near the dominant perforators, contributing to increased perfusion security. Conclusions High-frequency CDUS enables reproducible preoperative localisation of dominant IAICAP and LAICAP perforators and shows high agreement with intraoperative findings. Standardised ultrasound mapping may support structured flap planning and intraoperative orientation in oncoplastic breast reconstruction.

Introduction The emergence of large language models heralds a new chapter in natural language processing, with immense potential for improving medical care and especially medical oncology. One recent and publicly available example is Generative Pretraining Transformer 4 (GPT‐4). Our objective was to evaluate its ability to rephrase original surgical reports into simplified versions that are more comprehensible to patients. Specifically, we aimed to investigate and discuss the potential, limitations, and associated risks of using these simplified reports for patient education and information in gynecologic oncology. Material and Methods We tasked GPT‐4 with generating simplified versions from n = 20 original gynecologic surgical reports. Patients were provided with both their original report and the corresponding simplified version generated by GPT‐4. Alongside these reports, patients received questionnaires designed to facilitate a comparative assessment between the original and simplified surgical reports. Furthermore, clinical experts evaluated the artificial intelligence (AI)‐generated reports with regard to their accuracy and clinical quality. Results The simplified surgical reports generated by GPT‐4 significantly improved our patients' understanding, particularly with regard to the surgical procedure, its outcome, and potential risks. However, despite the reports being more accessible and relevant, clinical experts highlighted concerns about their lack of medical precision. Conclusions Advanced language models like GPT‐4 can transform unedited surgical reports to improve clarity about the procedure and its outcomes. It offers considerable promise for enhancing patient education. However, concerns about medical precision underscore the need for rigorous oversight to safely integrate AI into patient education. Over the medium term, AI‐generated, simplified versions of these reports—and other medical records—could be effortlessly integrated into standard automated postoperative care and digital discharge systems. Artificial intelligence (AI)‐driven simplification of medical reports holds promise for improving patient education. However, careful attention must be paid to ensuring accuracy and completeness. Use of AI technologies in healthcare will continue to expand but will require rigorous oversight and ongoing research to fully realize their potential in clinical practice.

Objective. The aim of this study was to assess the potential risks of interactions between biologically based complementary and alternative medication (BB-CAM) and conventional drugs during systemic therapy in breast and gynecological cancer patients by analyzing the actual CAM-drug combinations from individual patients’ records. Methods. From September 2014 to December 2014 and from February 2017 to May 2017, all patients (n = 717) undergoing systemic therapy at the Gynecologic Oncology Day Care Unit in the Gynecology and Obstetrics Department of the Technical University of Munich, Germany, were asked to participate in a questionnaire about all their medications. To assess the potential risk of CAM-drug interactions (CDIs), we initially utilized the Lexicomp drug interaction database. This assessment was then expanded with a systematic search of other digital databases, such as the National Center for Complementary and Integrative Health, Memorial Sloan Kettering Cancer Center, PubMed, and MEDLINE as well as the Cochrane Library. Results. Among 448 respondents, 74.1% reported using BB-CAM simultaneously with their systemic therapy. The assessment showed 1 patient with a potentially clinically relevant CDI, where the interaction was based on a self-medicated combination of Echinacea and cyclophosphamide. Furthermore, 81 patients (18.1%) were thought to have interactions because of a combination of BB-CAMs and cytochrome P450 3A4–metabolized anticancer drugs. Conclusions. Our data demonstrated high overall use of BB-CAMs by cancer patients undergoing systemic therapy. The analyses showed only 1 clinically relevant CDI.

Background There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. Methods The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. Results A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers ( BRCA1 : n  = 118, 14.7%; BRCA2 : n  = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p  < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. Conclusions Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.

Alfons Meindl and colleagues report heterozygous germline mutations in RAD51C in families with breast and ovarian cancer. Mutations were found in 1.3% of 480 pedigrees with breast and ovarian cancer, but not in 620 pedigrees with breast cancer only. Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia–like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis.

Background Patients who actively engage in their medical decision-making processes can experience better health outcomes. This exploratory study aimed to identify predictors of preferred and actual roles in decision-making in healthy women with BRCA1/2 pathogenic variants (PVs). Methods Women with BRCA1/2 PVs without a history of breast and/or ovarian cancer were recruited in six centres across Germany. Those returning the baseline questionnaires (T1) were randomly assigned to the intervention or control group (IG, CG). The IG completed a decision-coaching (DC) programme, the CG received standard care. A second survey (T2) followed after 12 weeks. Ordinal regression analyses were performed. Sociodemographic and outcome-related baseline variables were used to identify predictors of (i) desired role at T1 in the total group and (ii) actual role at T2 in the CG and the IG. Role preferences were measured with the Control Preferences Scale. Results 389 women completed the baseline questionnaires, 191 were randomised to the CG and 198 to the IG. At T1, high decisional conflict (OR 1.016, 95% CI 1.001–1.023, p  = 0.038) and a negative self-concept (OR 1.030, 95% CI 1.008–1.054, p  = 0.009) were significant predictors for preferring a more passive role. At T2, high baseline decisional conflict significantly predicted taking a more passive role in the CG, whereas in the IG, baseline decisional conflict showed no influence. Furthermore, in the IG, younger age (OR 1.049, 95% CI 1.001–1.098, p  = 0.044) and a non-academic education (OR 0.46, 95% CI 0.213–0.775, p = 0.006) were identified as significant predictors for taking a more active role. Conclusions High initial decisional conflict was identified as an important predictor for preferring and taking a passive role in decision-making among women with BRCA1/2 PVs. Participating in the DC programme can counteract passivating effects of an initially high decisional conflict and particularly support younger PV carriers and those with lower educational status to take an active role. With this profile, the DC programme expands the existing counselling and care concept to include a measure that can also specifically cover the support needs of younger women and those with a lower education level. Trial registration DRKS-ID: DRKS00015527. Registered 30/10/2019.